Swedish National Registers I have collaborated with Fang Fang and Weimin Ye at the Karolinska Institute on studies based on the Swedish National Registers. ALS and cancer: We studied 5,481 ALS cases from the Swedish Patient Register and 27,405 population controls. Overall, a previous cancer diagnosis was not associated with ALS risk either for all cancers or for any specific cancer although increased risk of ALS was observed during the first year after cancer diagnosis (OR 1.5, 95% CI 1.2-1.9). In contrast, a lower risk of cancer was observed in ALS patients after diagnosis compared to ALS-free individuals (IRR 0.8; 95% CI 0.7-1.0). Our results provide little evidence for comorbidity of cancer and ALS; surveillance bias seems the most likely explanation for the limited associations previously detected. ALS and diabetes: Energy metabolism is altered in patients with (ALS). We studied the association of diabetes with ALS in 5,108 ALS cases and 25,540 individually matched population controls during 1991-2010. Information on ALS and pre-existing diabetes was retrieved from the nationwide Swedish Patient Register. Diabetes was inversely associated with ALS risk (OR=0.79, 95% CI 0.68-0.91). The inverse association was stronger for non-insulin-dependent diabetes (OR=0.66, 95% CI 0.53-0.81) than for insulin-dependent diabetes (OR=0.83, 95% CI 0.60-1.15) and was noted only among individuals age 70 or older. For younger individuals (<50 years), preexisting insulin-dependent diabetes was associated with a higher risk of ALS (OR=5.38, 95% CI 1.87-15.51). Our study provide important evidence for an association between premorbid diabetes and ALS, highlighting also the importance of taking into account age, insulin dependence and diabetes duration when examining such an association. Occupational Cohorts Certain occupations and occupational exposures may be related to ALS, but data are sparse and inconsistent. Our results from the New England ALS study identified several associations with ALS. To extend this work, we collaborated with Lynne Pinkerton at NIOSH to study two cohorts. Formaldehyde: We studied ALS mortality in a cohort of 11,022 US garment workers exposed to formaldehyde. We ascertained vital status through 2008 and conducted life table analyses to obtain standardized mortality ratios. We observed 8 deaths from ALS. Compared to the US general population, ALS mortality was not elevated in the overall cohort or among subgroups with greater exposure based on exposure duration or year of first exposure. These results suggest that ALS is not associated with formaldehyde exposure but need confirmation in a larger study. Flight Attendants: Concern exists about the potential chronic neurological effects among flight crew of exposure to contaminants from engine oil in aircraft cabin air. We evaluated mortality from neurodegenerative diseases among 11,311 former US flight attendants. We ascertained vital status through 2007 and conducted life table analyses to obtain standardized mortality ratios. ALS mortality was elevated two-fold compared to the US population, based on 9 deaths. There was no clear pattern in risk related to exposure duration. Mortality from other neurodegenerative diseases was not elevated. Our findings are limited due to small numbers of observed deaths, but suggest that flight attendants may have an increased risk of ALS, possibly related to exposure to tricresyl phosphates in engine oil. GENEVA (Genes and Environment in Veterans with ALS) Reports that ALS risk might be increased among veterans deployed to the 19901991 Persian Gulf War prompted the Department of Veterans Affairs (VA) to establish a National Registry of Veterans with ALS. The registry, established in 2004, enrolled 1,573 US veterans with neurologist-confirmed ALS. Information in the VA Registry includes ALS diagnosis and other clinical details based on medical record review and information gathered during an initial screen and six-month follow-up interviews. Mortality has been ascertained through July 31, 2013. GENEVA is a case-control study comparing 631 ALS cases from the VA registry and 975 matched veteran controls. A structured telephone interview conducted collected information on demographics, lifetime occupational history, hobbies, home pesticide use, use of tobacco, caffeine, and alcohol, residential history, physical trauma, and family history of ALS or other neurodegenerative diseases. We conducted an add-on study, Veterans with ALS and Lead Exposure (VALE), to evaluate the relationship of blood lead to ALS. We collected whole blood samples in metal-free tubes from 200 ALS cases and 229 matched controls. We measured metals with inductively coupled plasma mass spectrometry, a highly sensitive assay, and evaluated bone turnover using biomarkers of bone formation and resorption. We found that age-adjusted blood lead levels were higher among cases compared with controls. Bone resorption was also greater in cases than controls, although bone formation was the same. ALS was associated with blood lead levels; the OR for each unit increase in log-transformed blood lead was 2.6 (1.9-3.7). The association persisted after adjustment for or stratification by bone turnover biomarkers. These results corroborate our earlier finding that elevated blood lead is associated with increased ALS risk and suggest that increased bone turnover in ALS cases does not fully explain this association. We are presently using VALE data to evaluate the relationship of blood lead to survival. Initial results suggest at best a weak association, consistent with that observed in the New England study. Of great interest is the fact that increased CTX, a marker of bone resorption, was associated with shorter survival, even after controlling for physical activity and respiratory function. Elevated CTX may be a clinically useful marker of prognosis. We are also using VALE data to evaluate the relationships other metals with ALS risk and survival. Military Exposures: Studies suggesting increased ALS risk among veterans of the first Persian Gulf War and potentially all military veterans provided the impetus for development of the VA ALS registry on which GENEVA is based. Detailed data on military service (eg, war, if any, years of service, military branch, etc) and military-specific exposures was collected in the GENEVA interviews. We plan to evaluate associations of these military exposures with ALS risk and survival. We will investigate (i) military service by branch and war; (ii) deployment-specific exposures, including several unique to the first Persian Gulf War; (iii) specific exposures including pesticides. Occupational Exposures: A complete occupational history was collected from GENEVA participants. Susan Woskie, an industrial hygienist, and a team of specialists are evaluating these histories in order to assign exposures to several agents of interest, all of which have been implicated in ALS by one or more studies but none conclusively. These exposures include lead, mercury, selenium, arsenic, PCBs, hydrocarbon solvents, chlorinated solvents, formaldehyde, EMF, and viral agents. Metabolic dysfunction: ALS patients are hypermetabolic. We are studying the relationship of body mass index (BMI) to ALS. Results to date indicate that BMI is reduced in cases, confirming earlier reports, and that BMI before diagnosis is also reduced. The association was stronger in patients with rapidly progressing disease, and higher BMI was associated with longer survival.